1. Field of the Invention
This invention relates to memory enhancement in patients suffering from illnesses consisting of amnesia, head injuries, Alzheimer's disease, epileptic dementia, presenile dementia, post traumatic dementia, senile dementia, vascular dementia and post-stroke dementia or individuals otherwise seeking memory enhancement. More particularly, the invention relates to the enhancement of memory by steroid sulfatase inhibitors and steroid sulfatase inhibitors in combination with the naturally occurring neurosteroids dehydroepiandrosterone sulfate (DHEAS) and pregnenolone sulfate (PS) and other structurally similar organic compounds.
2. Description of the Prior Art
Neurosteroids are concentrated within and are known to produce effects mediated by the central nervous system (CNS). Paul Robel and Etienne-Emile Baulile, Neurosteroids, Biosynthesis and Function, Trends Endocrinol Metab., Volume 5, pp. 1-8 (1994), disclose that several neurosteroids are involved in either auto-or paracrine mechanisms involving both regulation of target gene expression and effects on membrane receptors (including those of neurotransmitters).
Among the effects associated with neurosteroids is the enhancement of memory. James F. Flood, Gary E. Smith and Eugene Roberts, Dehydroepiandrosterone and Its Sulfate Enhance Memory Retention in Mice, Brain Research, Volume 447 pp. 269-278 (1988); James F. Flood, John E. Morley and Eugene Roberts, Memory-Enhancing Effects in Male Mice of Pregnenolone and Steroids Metabolically Derived From It, Proc. Nat'l Acad. Sci. USA, Volume 89, pp. 1567-1571 (1992) and James F. Flood and Eugene Roberts, Dehydroepiandrosterone Sulfate Improves Memory in Aging Mice, Brain Research, Volume 448, pp. 178-181 (1988).
The mechanism of this enhancement is not well understood but sulfated neurosteroids which enhance memory such as pregnenolone sulfate (PS) and dehydroepiandrosterone sulfate (DHEAS) are known to both inhibit the actions mediated by the GABA.sub.A receptor and facilitate NMDA receptors. The unsulfated analogs, pregnenolone and dehydroepiandrosterone, also enhance memory, however, they can also be metabolized to neurosteroids which have the opposite effect at the GABA.sub.A receptor. Synthia H. Mellon Special Article Neurosteroids: Biochemistry, Modes of Action and Clinical Relevance, Endocrinology and Metabolism, Volume 78, No. 5 pp. 1003-1008 (1994) and Majewska M.D.: Neurosteroids: Endogenous Bimodal Modulators of the GABA.sub.A Receptor. Mechanism of Action and Physiological Significance. Progress in Neurobiology, Volume 38, pp. 379-395 (1992).
PCT/US 92107739 published as WO93/04687 on Mar. 18, 1993 discloses methods for modulating NMDA-mediated ion transport and inhibiting non-NMDA glutamate-induced ion transport in neuronal cells. The methods involve contacting a neuronal cell with an effective mount of the neurosteroid pregnenolone sulfate and PCT/US92/08935 published as W093/07877 on Apr. 29, 1993 discloses memory enhancement by pregnenolone and pregnenolone sulfate. PCT/GB92/01587 published as WO/93/05064 on Mar. 18, 1993 disclosed that steroid sulfatase inhibitors are able to treat breast cancer.
Since the metabolism of pregnenolone and DHEA between the sulfated and unsulfated forms occurs bi-directionally within the central nervous system, it was previously unknown whether the sulfated or unsulfated forms produce memory enhancing effects individually or by way of metabolism from one analog to the other.
Therefore, in spite of the prior art disclosures, there remains a very real and substantial need for asteroid sulfatase inhibitor which can alter the equilibrium between the endogenous sulfated and unsulfated forms of DHEA in such a way to enhance memory. There is also a need to determine whether the memory enhancing effects of peripherally administered DHEAS and PS can be potentiated by inhibition of the metabolism of DHEAS and PS to DHEA and P, respectively, by way of preadministration of the steroid sulfatase inhibitors of the present invention.